Prostate cancer and neuroendocrine differentiation: more neuronal, less endocrine?

Abstract

Neuroendocrine differentiation (NED) marks a structural and functional feature of certain cancers, including prostate cancer (PCa), whereby the malignant tissue contains a significant proportion of cells displaying neuronal, endocrine, or mixed features. NED cells produce, and can secrete, a cocktail of mediators commonly encountered in the nervous system, which may stimulate and coordinate cancer growth. In PCa, NED appears during advanced stages, subsequent to treatment, and accompanies treatment resistance and poor prognosis. However, the term "neuroendocrine" in this context is intrinsically vague. This article seeks to provide a framework on which a unified view of NED might emerge. First, we review the mutually beneficial interplay between PCa and neural structures, mainly supported by cell biology experiments and neurological conditions. Next, we address the correlations between PCa and neural functions, as described in the literature. Based upon the integration of clinical and basic observations, we suggest that it is legitimate to seek for true neural differentiation, or neuromimicry, in cancer progression, most notably in PCa cells exhibiting what is commonly described as NED.

Keywords: chromogranin A; interleukin-6; neural differentiation; neuroendocrine differentiation; prostate cancer.

Figure 1

Prostate cancer displaying focal neuroendocrine differentiation. Focal NED typically requires specific staining methods. However, in about 10% of cases, NE cells display large eosinophilic granules recognizable by conventional staining (arrows). In focal NED, the NE cells occur either as solitary cells or in clusters. H&E stain. Courtesy and with permission of Dharam M. Ramnani, MD; WebPathology.com.

Figure 2

Prostate cancer displaying universal neuroendocrine differentiation. Universal NED is synonymous to SCCP. This cancer type is rarer than conventional prostatic adenocarcinoma (fewer than 1% of total PCa cases) and prognosis is dismal. Histologically, cells display scarce cytoplasm, hyperchromatic nuclei with finely dispersed chromatin and inconspicuous nucleoli, and nuclear molding. Mitotic index is high and necrosis often is present. In about half of the cases, the small cell carcinoma is admixed with areas of conventional prostatic adenocarcinoma. The Gleason scale cannot be used for pure SCCP, but in mixed cases it should be used to grade the adenocarcinoma regions. H&E stain. Courtesy and with permission of Dharam M. Ramnani, MD; WebPathology.com.

Figure 3

Neuroendocrine differentiation spans a continuous and dynamic range. Conventional prostatic adenocarcinoma, focal NED, and SCCP traditionally are represented as separate entities, but evidence shows that they rather form a unique spectrum of prostatic malignancies. The common denominator encompasses two parameters: the extent of NED (green gradient), spanning from zero (conventional prostatic adenocarcinoma) to universal NED (SCCP), and the extent of malignant dissemination (red gradient), ranging from localized to metastatic disease. During first presentation or reoccurrence, NED can be diagnosed at any point across this plane (black human icons). For any patient, any parameter can shift to a higher value at any stage during the course of the disease (see color-coded arrows, each color corresponding to one patient), but no parameter shifts to a lower value (gray arrows crossed by red saltires). Loc, localized disease; Met, metastatic disease; ADK, conventional prostatic adenocarcinoma; NED, focal NED; SCCP, small cell carcinoma of the prostate.

Figure 4

Small cell carcinomas are a large, homogeneous family of cancers. The histology, therapeutic regimens, response to therapy, and prognosis of SCCP are strikingly similar to small cell carcinomas of all the other organ sites, including SCLC shown here. Extensive nuclear molding and apoptotic bodies can be seen. See Figure 2 for comparison with SCCP. H&E stain. Courtesy and with permission of Dharam M. Ramnani, MD; WebPathology.com.

Figure 5

Prostate cancer immunostaining for neuroendocrine markers. In surgical or core needle biopsy samples, NED can be detected by immunostaining against specific markers, most notably peptides, which are present inside the NE secretory vesicles (see text for details). A frequently used NED marker is the enzyme NSE, seen here as brown cytoplasmic granules. Immunoperoxidase stain. Courtesy and with permission of Dharam M. Ramnani, MD; WebPathology.com.

Figure 6

Neuraxial anesthesia/analgesia as a “temporary spinal cord injury.” (A) At the micro level, neurons (left) and prostate cancer cells (right) engage in a symbiotic, mutually growth-supportive relationship (green arrows). One NE cancer cell, displaying secretory granules, also is depicted between the non-NE cells. (B) (Left) At the macro level, sensory prostatic neurons (blue), but not motor prostatic neurons (magenta) support growth of the prostate gland (green arrow). (Middle) At the macro level, SCI (oblique black bar) disrupts prostatic innervation (dashed sensory and motor prostatic neurons), which consequently impairs growth and reduces (red saltire) the risk for developing PCa (light purple oval). (Right) During PCa surgery, NAA also disrupts prostatic sensory innervation (dashed sensory prostatic neurons) by pharmacologic blockade (oblique red bar-headed line), which reduces risk (red saltire) for recurring PCa (dotted light purple oval line). It is thus reasonable to infer that NAA induces a “temporary SCI” that inhibits PCa similarly to SCI-induced sensory neuronal damage (see text for details). N, neurons; PCa, prostate cancer; SC, spinal cord; P, prostate; SCI, spinal cord injury; NAA, neuraxial anesthesia/analgesia.